There is no broader topic in mammalian genetic research than human disease. Literally thousands of human diseases, disorders and syndromes have been described and through advances in genome technologies, are being characterized in much greater molecular detail. Now, a fundamental challenge for medical research is to develop and exploit the most relevant and predictive model systems to understand the physiological impact of this genetic variation, with the ultimate goal of improving patient care and treatment. Already in the past two decades, the range of approaches used to study gene function in normal and diseased states has increased dramatically. However, as our depth of knowledge has grown so too have our expectations - both in the accuracy of experimental models to recapitulate human conditions, as well as the speed and scope at which they can be applied to ask biological questions. The MSKCC Pilot Center for Precision Disease Modeling was conceived to take up this challenge, and will unite and expand existing infrastructure and research to create an innovative center with the ability to effectively utilize genomic information in vivo models, and preclinical and co-clinical studies to enhance the understanding and treatment of disease. The Center will include two Cores: a Preclinical/Co-Clinical Core consisting of Genomic, Mouse Modeling, and Mouse Hospital Units and a Bioinformatics Core. These highly integrated core resources will be used to support three Disease Modeling Units that serve as pilot projects to illustrate and help hone the capabilities of the Center. Each of th Disease Modeling projects address significant and innovative basic, translational, and clinical questions relevant to the understanding and treatment of diseases, ranging from the mechanistic basis for early bone marrow failure in premature aging syndromes, the molecular origins and dependencies of colorectal cancers, and the development of precision treatment strategies for patients with acute leukemia. The major goals of the MSKCC Pilot Center for Precision Disease modeling are to: (1) Coordinate and enhance ongoing genomics, computational, and animal modeling efforts at MSKCC to produce an integrated Pilot Center for Precision Disease Modeling; (2) Provide technical infrastructure and support for the Center's Disease Modeling Units; and (3) Make available Center capabilities to MSKCC investigators and other NYC institutions. Additionally, the Center will work with the NIH and other pilot centers to leverage resources to achieve the greatest national impact. In summary, the center will provide a blueprint for realizing the potential of human genomics to guide the development of accurate models that can be use to develop novel therapies to ameliorate disease.